DESCRIPTION: Apoptosis or programmed cell death is a process of cell auto-destruction that eliminates unwanted, severely damaged, or potentially harmful cells. Apoptosis mediated by a group of cell surface proteins known as the death receptors plays important roles in the regulation of immune responses and immune surveillance of tumor. These receptors include tumor necrosis factor receptor 1 (TNFR1), Fas, death receptor (DR) 3 to 5. Both defective and excessive death receptor signaling cause human disease, ranging from autoimmune disorders to diabetes, hepatitis, and cancer. We have identified Daxx, a novel Fas signaling protein. Daxx induces apoptosis through activation of the c-Jun N-terminal kinase (JNK) pathway; and it directly binds to and activates an apex kinase of the JNK pathway, ASK1. Daxx is predominantly present in distinct subnuclear structures known as nuclear bodies (NBs) or nuclear domain 10 (ND 10). A few other apoptosis proteins, including the tumor suppressor protein PML, are also located at thhe NBs. We propose to further investigate the role of Daxx in death receptor signaling and apoptosis. Specifically, we will determine the involvement of Daxx in the signaling of the other death receptors and the mechanisms by which Daxx activates cell death. These studies should further our understanding of apoptosis regulation and lead to the new effective therapeutic approaches to treat related diseases.